The long-term objective of this research is to identify the biochemical lesion(s) responsible for cell damage following ischemia. What the pathogenic event is, as well as where and when it occurs, has been the subject of some controversy. The fate of the tissue may be determined during ischemia, but there is also evidence that reintroduction of oxygen and glucose during recirculation elicits a unique metabolic response suggesting that the recovery process following ischemia is more than a reversal of ischemia-induced events. The recent observation that following 5 minutes of bilateral ischemia the CA 1 pyramidal neurons of the hippocampus die at 4 days of recirculation provides an excellent model for the investigation of the biochemical events that precede cell death. The proposed experiments are designed 1) to examine the effects of near-complete ischemia on long-term recovery in discrete brain regions which exhibit varying degrees of vulnerability to ischemia and 2) to test a number of hypotheses concerning the underlying causes of ischemic cell death. In these in vivo experiments, the concentrations of high-energy phosphates, glucose metabolites, certain amino acids and the cyclic nucleotides will be measured in the somal layer of the CA 1 and CA 3 region of the hippocampus as well as in a portion of the cerebral cortex at various intervals for up to 7 days of recirculation. The tissue samples weigh less than 1 ug and will require the use of microquantitative histochemical methods for the measurement of the metabolites. The discrete sampling of tissue should provide a more precise determination of the actual changes that occur within the affected tissue. Variations on this model of selective vulnerability including longer periods of ischemia, pentobarbital treatment and hyperglycemia will also be examined. The results should define the pathophysiology associated with neuronal death and provide additional insight into the long-term recovery process. The latter should give a temporal and a biochemical basis for the testing of novel therapeutic approaches during recirculation.